Of the estimated 55 million Pap smears performed each year in the United States, more than 5% are reported as abnormal (ALTS study 2003). An estimated 800,000 women each year present with low-grade squamous intraepithelial lesions (LSIL) (Jones. B A. Davey D D. Quality management in gynaecologic cytology using interlaboratory comparison. Arch. Pathol. Lab. Med. 2000; 124(5):672-81).
These lesions will either progress with time to cervical intraepithelial neoplasia (CIN) 2-3 or invasive cancer, especially in women that present with the high-risk HPV-subtype, or regress with time in the absence of treatment. Of women diagnosed with LSIL, 25% will progress to CIN grade 2 or 3, 22-32% will have persistent CIN 1 and approximately 50%-70% will experience spontaneous regression of LSIL within 2 years (ALTS group 2003; Östör A G, Natural history of cervical intraepithelial neoplasia: a critical review. Int. J. Gynecol. Pathol. 1993, 12:186-92). Approximately 75% will experience spontaneous regression within 5 years.
Previously, U.S. Ser. No. 12/532,752 disclosed biphasic compositions for treating women with human papilloma virus (HPV) presenting with LSIL. These compositions represented a first-in-class treatment protocol and show significant promise. The biphasic compositions disclosed therein employ interferon alpha-2b in an oil-in-water emulsion which is found in both the intra-vesicular and extra-vesicular phases. The interferon in both phases is oxidatively stabilized by the addition of methionine which unexpectedly partitions preferentially into the aqueous portion of the emulsion. Additionally, as disclosed in the U.S. Provisional Application No. titled “Biphasic Lipid-Vesicle Compositions and Methods for Treating Cervical Dysplasia by Intravaginal Delivery,” having U.S. Ser. No. 13/965,122 and filed concurrently on same date, the entirety of which is herein incorporated by reference, addition of a pharmaceutically acceptable salt of arginine increases the shelf life of the compositions. However, notwithstanding the benefits of such compositions, the lipid oxidative stability of these biphasic compositions remains a limiting factor in providing even longer shelf-life of the lipid portion of these compositions. Without being limited to any theory, lipid oxidation can result in premature disruption of the vesicles.
Accordingly, it would be desirable to provide for improved compositions having sufficient integrity to maintain the biphasic lipid vesicle structure for extended periods of time so as to provide for enhanced shelf-life of the composition.